MRPL21 is a structural component of the mitochondrial ribosome, or mitoribosome, which carries out protein synthesis inside the mitochondrion. Mammalian mitoribosomes consist of a small 28S subunit and a large 39S subunit, and the MRPL21 protein is part of the 39S large subunit. Mitoribosomes have an estimated 75% protein to rRNA composition, whereas this ratio is reversed in prokaryotic ribosomes, and unlike prokaryotic ribosomes they do not contain a 5S rRNA.

The MRPL21 gene is nuclear, not mitochondrial, so the protein is made in the cytoplasm and then reaches the mitochondrion, its annotated subcellular location. It belongs to the bacterial ribosomal protein bL21 family, which is reflected in its systematic name, large ribosomal subunit protein bL21m. Mitoribosomal proteins differ greatly in sequence between species, and sometimes in biochemical properties, so they are not easily recognised by sequence homology. Mouse has an ortholog named Mrpl21. Sequence analysis of the MRPL21 gene has identified multiple transcript variants encoding different isoforms, although some may be subject to nonsense-mediated decay.

HGNC places MRPL21 in the mitochondrial ribosomal proteins group, within the large subunit mitochondrial ribosomal proteins. Researchers working on mitochondrial translation, mitoribosome assembly and the nuclear-mitochondrial coordination of gene expression study MRPL21 alongside other 39S subunit proteins. The MRPL21 antibody and MRPL21 protein reagents are used in this context.